Titin's cardiac-specific N2B element is critical to mechanotransduction during volume overload of the heart.

Autor: Strom J; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, United States of America; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85721, United States of America., Bull M; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, United States of America; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85721, United States of America., Gohlke J; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, United States of America; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85721, United States of America., Saripalli C; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, United States of America; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85721, United States of America., Methawasin M; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, United States of America; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85721, United States of America., Gotthardt M; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of Cardiology, Charité-Universitätsmedizin Berlin, Berlin, Germany., Granzier H; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, United States of America. Electronic address: granzier@arizona.edu.
Jazyk: angličtina
Zdroj: Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2024 Jun; Vol. 191, pp. 40-49. Date of Electronic Publication: 2024 Apr 10.
DOI: 10.1016/j.yjmcc.2024.04.006
Abstrakt: The heart has the ability to detect and respond to changes in mechanical load through a process called mechanotransduction. In this study, we focused on investigating the role of the cardiac-specific N2B element within the spring region of titin, which has been proposed to function as a mechanosensor. To assess its significance, we conducted experiments using N2B knockout (KO) mice and wildtype (WT) mice, subjecting them to three different conditions: 1) cardiac pressure overload induced by transverse aortic constriction (TAC), 2) volume overload caused by aortocaval fistula (ACF), and 3) exercise-induced hypertrophy through swimming. Under conditions of pressure overload (TAC), both genotypes exhibited similar hypertrophic responses. In contrast, WT mice displayed robust left ventricular hypertrophy after one week of volume overload (ACF), while the KO mice failed to undergo hypertrophy and experienced a high mortality rate. Similarly, swim exercise-induced hypertrophy was significantly reduced in the KO mice. RNA-Seq analysis revealed an abnormal β-adrenergic response to volume overload in the KO mice, as well as a diminished response to isoproterenol-induced hypertrophy. Because it is known that the N2B element interacts with the four-and-a-half LIM domains 1 and 2 (FHL1 and FHL2) proteins, both of which have been associated with mechanotransduction, we evaluated these proteins. Interestingly, while volume-overload resulted in FHL1 protein expression levels that were comparable between KO and WT mice, FHL2 protein levels were reduced by over 90% in the KO mice compared to WT. This suggests that in response to volume overload, FHL2 might act as a signaling mediator between the N2B element and downstream signaling pathways. Overall, our study highlights the importance of the N2B element in mechanosensing during volume overload, both in physiological and pathological settings.
Competing Interests: Declaration of competing interest The authors have declared that no conflict of interest exists.
(Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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